Principal Investigator/Program Director (Last, first, middle): Wilson, Teresa, M PROJECT SUMMARY/ABSTRACT The most important risk factor for the development of colorectal cancer is age: greater than 90% of people diagnosed with colorectal cancer are 50 or older. A gender-based difference exists as well. With considerations for age and race/ethnicity, colorectal cancer incidence and mortality rates are more than 35% higher in men than in women. Age and gender also affect the occurrence of microsatellite instability (MSI), a hallmark of defects in the mismatch repair pathway (MMR), in both sporadic and inherited colorectal tumors. Women in general are less likely than men to have MSI positive tumors at a young age, a trend that is maintained in older women undergoing hormone replacement therapy. The MMR pathway performs a critical role in the maintenance of genomic stability by repairing mismatches and insertion/deletion loops in DNA and by signaling for programmed cell death in response to DNA damage. We have found that MMR deficient cells are more resistant to apoptosis and cell death induced by treatment with estrogen. Additionally, we have found that estrogen enhances the interaction between the estrogen receptor beta (ER), the major ER isoform in the colon, and the MMR lesion recognition complexes. The main goal of this proposal is to test the hypothesis that ER, estrogen, and the human mismatch repair proteins function together to maintain genomic integrity. This will be accomplished in three Specific Aims: (1) Specific Aim 1 will test the hypothesis that estrogen and ER enhance the mismatch repair-dependent cellular response to DNA damage; (2) Specific Aim 2 will test the hypothesis that E2 and ER enhance MMR DNA repair activities; and (3) Specific Aim 3 will test the hypothesis that the MMR proteins modulate the biochemical activities of ER. Project Description Page 6